Tumor-stroma interaction contributes significantly to localized cancer growth, invasion and distant metastasis. The purpose of this proposal is to study the biology of this interaction and the potential molecular targeting of prostate cancer bone metastasis. The proposal focuses on three themes. First, molecular interaction between stromal extracellular matrix (ECM) and cancer epithelium is responsible for increased prostate cancer growth and its potential for distant dissemination. We will assess the potential roles of stromal ECM in inducing prostate cancer cell growth, survival and invasion. Second, in response to tumor epithelium, permanent genetic, phenotypic and behavioral alterations are induced in prostate fibromuscular stromal cells and marrow stromal and proliferating osteoblasts. By evaluating these molecular changes, novel stromal signatures may be revealed that will be useful markers for early cancer diagnosis and prognosis. Third, ECM-cell surface integrin interaction will be co-targeted for the treatment of prostate cancer bone metastasis. These inter-related themes will be examined systematically with the goal of understanding the biology of tumor-stroma interaction and developing modalities of mechanism-based molecular targeting of prostate cancer bone metastasis. Specific Aims of this Project are: Aim 1: We will define the genotypic and phenotypic changes of prostate stromal fibroblasts and osteoblasts in response to inductive prostate tumor epithelium. By focusing the activation of osteocalcin promoter activity in prostate cancer and stromal fibroblast cells, we will assess the downstream signal "network" activated by ECM and soluble factor(s). We hypothesize non-random changes will occur in prostate stromal fibroblasts and osteoblasts in response to inductive influence from prostate tumor epithelium. Aim 2: We will develop new transgenic mouse models for prostate cancer bone metastasis. The hypothesis that stromal ECM served as chemoattractants to induce local cancer growth, invasion, and distant metastasis will be tested. We propose that physical interaction and the usage of specific integrins upon contact with ECM may contribute to tumor growth, invasion and survival in bone. Aim 3: We will design a molecular co-targeting strategy for tumor growth in bone. We hypothesize that interrupting the ECM-integrin interaction between tumors and stroma will abolish pre-existing prostate tumor growth and its subsequent metastasis to bone.